One of the challenges facing oncology in the 21st century is the individualization of patient care. Tumors, even of the same type, have a wide range of presentation and a wide range of responses to both standard and novel therapies. Genotyping prior to therapy is showing great promise in allowing a choice of therapies for individual patients. After treatment has begun, however, methods to non-invasively detect the early response (or non-response) of individual tumors to therapy would be important to the overall goal of improved care for the individual patient. Hence, responders could be continued on successful therapy, and non-responders could be discontinued on ineffective and toxic therapy and moved to alternative therapies. The overall hypothesis of this project thus states that non-invasive imaging modalities can monitor the response of individual patients to therapy. In the context of the current proposal, non-invasive imaging can help develop and optimize novel therapeutic agents through the use of surrogate endpoints that are highly sensitive to the molecular target. Imaging methods are currently available which allow end-point assessment of therapeutic efficacy and these will be useful in assessing treatment protocols in pre-clinical and clinical settings. Additional imaging and spectroscopic methods will allow more direct assessment of proximal molecular consequences of drug action, and these will be developed. The specific aims of this Project are therefore: 4.1 To monitor apoptosis in vivo using two non-invasive imaging modalities, Technetium-labeled Annexin V Imaging and diffusion Magnetic Resonance Imaging, which are both in clinical trials. Apoptosis is a common endpoint for all of the therapies used in this program. This will be performed in both animal models and in human patients. 4.2 In collaboration with project 3 using SU-5416 and thalidomide, to monitor therapeutic response to anti-angiogenic drugs using dynamic contrast-enhanced MR Imaging (DCE-MRI). This will be performed in both animal models and in human patients. 4.3 In collaboration with project I using DPIEL and Wortmannin, to use non-invasive magnetic resonance spectroscopy (MRS) to characterize the metabolic molecular signatures of tumor models before and after therapy with inhibitors of signal transduction. This will be performed in both animal models and in human patients.